Recent studies have revealed the importance of the gut associated lymphoid tissue (GALT) and its interaction with gut commensal bacterial population in the balance of peripheral immunity. We have shown that modifying bacterial populations of the gut can protect against EAE, the experimental model of human multiple sclerosis. Prophylactic and therapeutic oral administration of a highly purified, structurally characterized preparation of the bacterial antigen, polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis can protect against EAE in an IL-10 dependent mechanism. Of note, was a significant increase in both CD103+CD11Chigh GALT derived DC and FoxP3+Treg cells with concurrent downregulation of IL-17 in the CLN of protected mice, when compared to untreated controls. We hypothesize that specific gut commensal antigens, in particular capsular polysaccharide A (PSA) of the human commensal bacteria B. fragilis, when administered per os can protect against CNS demyelinating disease. Protection is mediated via TLR-2 ligation of mucosal DC or B cell populations that are polarized and migrate to the CNS and associated lymphoid tissue whereupon they induce disease-modifying regulatory T cells that control inflammation and demyelination. The specific aims are: 1) to identify and phenotype the APC associated with PSA immunization in EAE mice, 2) to identify the specific molecules involved in the migration and trafficking by PSA-associated APCs as well as T/B cells to the brain/spinal cord and CNS associated lymphoid tissues and 3) to determine the requirement of TLR2 in the induction of CD39+/- Tregs and B cells by PSA in the CNS and its associated lymphoid tissue. The innovation of this proposal is two-fold. First, it provides novel information on the immune interplay between commensal activated GALT and regulation of CNS inflammatory demyelination and second puts forth a novel probiotic approach as a potential therapeutic against this chronic debilitating disease with broad implications on the treatment of MS and other autoimmune conditions.